Modified Release Dosage Forms

Modified release dosage forms

Extended release Delayed release

- Sustained release
- Controlled release
Modified Release Dosage Forms
• Modified release is a general term that refers to any formulation that releases drug
other than immediately.
• The USP differentiates two kinds of modified release dosage forms: Delayed and
extended
1. Delayed release dosage forms
- These forms are designed to disintegrate in a location other than the stomach but
when they reach the location of release, they disintegrate rapidly to provide
maximal drug concentrations in the area of the gastrointestinal tract where they
dissolve. Enteric coatings with pH sensitive solubility are the most common design
to control where a delayed release dosage form disintegrates.
- When delayed release dosage forms disintegrate and dissolve, they will produce a
rapid rise in blood levels of the drug followed by a decline determined by the
ability of the blood to eliminate the drug.
Modified Release Dosage Forms

Delayed release dosage forms

- protect acid labile drugs from getting
degraded in the acidic environment of the
stomach
- protect the stomach lining from the irritant
effect of drugs
- remains intact in stomach, if the intended
site of drug release is intestine or colon.
Modified Release Dosage Forms
2. Extended release dosage forms are designed to release drug in a prolonged
or controlled manner, at a predetermined rate, duration, and location to
achieve and maintain optimum therapeutic plasma drug level. They allow at
least a two-fold reduction in dosing frequency as compared to the conventional
immediate release form.

Rationale/Advantages
• Extend/prolong the duration of action of the drug

• Reduce the frequency of dosing and hence, improve patient compliance

• Minimize the fluctuations in plasma drug level

• Because of fewer blood level peaks outside therapeutic range and into toxic
range, adverse side effects are less frequent.
Modified Release Dosage forms
• Extended release dosage forms: Are either sustained or controlled
release depending on whether the release of drug occurs in a
concentration dependent (first order) or concentration independent
(zero order) manner. Often the terms sustained and controlled release
are used interchangeably, however, there is a distinction.

• Sustained or first order drug release is characterized by a slow rise to

an initial peak and even slower decline in release rate, the rate
slowing as the amount of drug in the dosage form declines.

• A controlled release dosage form is able to provide a constant rate of

release for a predictable period of time, a model of release referred
to as zero order because the rate of drug release is independent of
the concentration of drug in the dosage form.
Modified Release Dosage forms
• Some modified release dosage forms display bimodal release in which
part of the dose is released in an immediate fashion and part is
released in a delayed or extended fashion.

- Number of diseases like schizophrenia require immediate release of drug for instant effect
to manage the panic attack at its presentation and then drug concentration has to be
maintained for prolong effect of the drug.
- On the basis of requirement for such a disease conditions, the multilayered tablet concept
has been utilized.
- Such a tablet has a fast releasing layer and may contain bi- or triple layers to sustain the
drug release.
- Bilayer tablets present a better choice where one layer provide immediate dose which
then maintains the plasma drug level by its controlled release layer of the tablet.
- Venlafaxine hydrochloride is a multilayered bimodal release tablet which is frequently
prescribed for management of panic depression attacks.
Delayed release dosage form designs
Delayed release dosage forms may be formulated to release their drug contents
for absorption in the small intestine or for release on the surface of the colon.
1. The most popular approach to design such dosage forms has been the use of
enteric coats, which are composed of acidic polymers that dissolve as the pH
of the intestine increases.
- There are a number of polymers that dissolve at a suitable range of pH that can
be used to coat either a compressed tablet or pellets or beads (multi-particulates).
- The methacrylic acid copolymers (Eudragit) are widely used to deliver an intact
dosage form through the stomach to the small or large intestine.
2. Another approach is to build a lag time into the dosage form with coatings that
slowly erode to release the drug at the time typical gastrointestinal transit would
carry it to the targeted location.
3. The third approach, the preparation of prodrugs that are cleaved to the active
agent by colonic bacteria, ensures that drug release is confined to the colon.
Extended Release Dosage Form Designs
The release of drug from an extended release dosage can be i) Dissolution controlled ii) Diffusion
controlled or, iii) Diffusion-Dissolution controlled

1. Dissolution controlled
Dissolution controlled extended release dosage form can be designed as a) Reservoir system b)
Matrix system

a. Reservoir System
In this system, a drug granules are surrounded by a slowly dissolving polymer film. Thickness
of polymer film may vary. The coated granules are then pressed into tablets or formed into
pellets and placed in capsules. The polymer dissolves slowly on contact with GI fluid, and
allows penetration of the GI fluid into the drug core and dissolution of the encapsulated drug,
prior absorption.

The drug release rate is controlled by

i. the properties of the polymer (e.g., polymer composition and molecular weight),
ii. the thickness of the polymer coating, and
iii. the physicochemical properties of the enclosed drug, such as solubility, drug particle size, and
molecular weight.
Figure: Diagrammatic representation of reservoir dissolution controlled system
1. Dissolution controlled

b. Matrix System
Drug is homogenously dispersed in a slowly dissolving polymer. The mixture of API, excipients
and polymer are compressed into a matrix tablet. The polymer slowly dissolves on contact with GI
fluid and allows dissolution of the entrapped drugs within the polymer matrix, prior absorption.

Surrounding GI fluid

Figure: Diagrammatic representation of matrix dissolution controlled system

 Extended Release Designs contd...
2. Diffusion Controlled
Diffusion controlled extended release dosage form can be designed as a) Reservoir system
b) Matrix system

a. Reservoir system
The drug core is coated with an insoluble semi permeable membrane (polymer) that
allows water into the dosage form and, once the drug has dissolved, allows it to diffuse out.

Membrane coatings may be applied to pellets or to single-unit tablet cores containing

drug.

Figure: Membrane encapsulated tablet Figure: Membrane encapsulated pellet. The

semipermeable membrane allows water to diffuse in and
drug to diffuse out
• The membrane of reservoir dosage forms may be composed of an insoluble semi
permeable membrane polymer such as ethylcellulose, or the membrane may be a
blend of insoluble and soluble polymers with the soluble polymers acting as pore-
forming agents.

• The soluble polymer component dissolves on contact with gastro-intestinal fluids

producing tiny pores in the membrane to allow the entry of water and the exit of drug
molecules.
Film Coating Technique for Sustained Release Dosage Forms
It involves the deposition of a uniform coat onto the surface of the substrate such as
compressed tablets, granules, nonpareil pellets, capsules. Water soluble polymers cannot be
used for film coating for release modification.

Enteric polymers
✓ Cellulose acetate phthalate
✓ Polyvinyl acetate phthalate
✓ HPMC phthalate
✓ HPMC succinate
✓ Methacrylic acid ester copolymers etc.

The water insoluble polymers such as—

✓ Ethyl cellulose
✓ Cellulose acetate
✓ Cellulose triacetate
✓ Cellulose acetate butyrate
2. Diffusion Controlled

b) Matrix system

• The drug is homogenously dispersed within an insoluble polymer and a channeling agent.

• The channeling agent dissolves on contact with GI fluid and create channels for entry of GI
fluid inside the tablet and release of drug. The channeling agent could be polymers like
polyethylene glycol.

• Insoluble polymers such as ethylcellulose, ammonio-methacrylate copolymer and

polypropylene may be used to prepare non-eroding matrix tablets, which allow drug to diffuse
out through channels once GI fluid has penetrated the matrix and dissolved the drug.

• Because the inert matrix tablets do not disintegrate they will appear in the patient’s stool.

Polymer

Dissolve drug coming out through channels

Drug dispersed within polymer

Channels

Figure: Inert matrix tablets. Water enters the tablet through the channels formed in the
inert matrix, and dissolved drug diffuses out
Extended Release Designs Contd…
3. Diffusion-dissolution controlled (Hydrogel Matrix System)

- Drug is homogeneously mixed with a swellable, water soluble polymer (e.g.

hydroxypropylmethyl cellulose, polyethylene oxide) and compressed into a single tablet
unit.

- The polymer swells on contact with gastrointestinal fluids and forms a gel-like
network of polymer fibers through which the drug must diffuse to be released. The
drug is released further once the outer hydrated gel layer erodes.

- Water soluble drugs are primarily released by diffusion through the gel layer and low
water soluble drugs or insoluble drugs are primarily released by tablet erosion
(dissolution). .

- The hydrophilic matrix tablet is currently the most common design used for extended
release in the industry.
Figure: Hydrophilic matrix tablets
4. Osmotic pump system

In the basic osmotic pump tablet, drug is loaded into an osmotic core along with
osmotic agent (fructose, NaCl, KCl, dextrose) and surrounded by a cellulose acetate
membrane that is permeable to water but not to drug or other solutes. As water is drawn
across the semi permeable membrane due to a concentration gradient, the osmotic
pressure pushes the dissolved drug out of the tablet in a zero order fashion through a
laser drilled hole.

Figure: Basic osmotic pump system

5. Ion exchange system
• Ion exchange system involve resins which are polymeric particles that contain basic or acidic
functional groups, and can form ionic complexes with oppositely charged drugs.
• Cation exchange resins contain covalently bound negatively charged functional groups and bind to
positively charged drugs.
• Anion exchange resins contain covalently bound positively charged functional groups and bind to
negatively charged drugs.

• Only ionic drugs can be released by this system.

• The resins are insoluble polymers and are not absorbed by the body. The release of the drug
depends on the pH and electrolyte concentration in the gastrointestinal tract.
• As the pH or ion concentration of the gastrointestinal tract changes, the charged group on the resin will
either lose its charge and release the drug, or the drug is released by exchange with a competing
ion from gastrointestinal fluids.

• Ion exchange technology may be used to prepare oral liquids as well as oral solid dosage forms. The
resin-drug complex may be suspended in oral suspension or compressed into tablets or
encapsulated.

• Ion exchange resins can mask bitter taste of drugs and reduce upper gastrointestinal side effects
because of limited release in the stomach.
Ion exchange conti..

Figure: Ion exchange drug delivery system

6. Gastric retention systems
• These dosage forms are designed to retain the drug in the stomach for a
long period of time to treat conditions such as Helicobacter pylori
infection or to provide longer exposure to drugs for localized therapeutic
action on colon.
• Drugs prepared in gastro-retentive dosage forms must be acid stable, and
the dosage form must be able to withstand the mechanical grinding
activity of the stomach.
• The three designs that appear most promising for gastro-retention are
floating dosage forms, bio-adhesive multi-particulates (mucoadhesion),
and swelling, single-unit systems.
• Swelling systems appear to be the most promising of the gastro-retentive
designs. These dosage forms are made with polymers that swell in the
stomach, becoming larger than the pyloric opening. They increase the
gastric retention for up to 16 hours.
Drug properties that influence design of
modified release dosage forms
The following properties influence the design of delayed and extended
release dosage forms.

1. Solubility:
• For drugs with good solubility there are many formulation options
for the design of extended release products.
• A drug with very low solubility may have inherently sustained
release due to its slow dissolution rate.

2. The drug must be sufficiently permeable to provide an absorption

rate that is faster than drug release from the dosage form.
Drug properties that influence design of
modified release dosage forms
3. Dose: It is essential that the daily dose of drug be sufficiently low that
one day’s dose will not be too large to swallow, the maximum
swallowable dose generally considered to be between 500 mg and 1g.

4. If a drug is inactivated by gut enzymes more rapidly than it is

released by the extended release dosage form, pre-systemic losses of
drug can be higher than with conventional release dosage forms.
 Characteristics of Drugs Unsuitable for Peroral
Sustained Release Dosage Forms
1. Those which are absorbed and excreted rapidly; short biological
2. half life(<1 hr). Ex- Penicillin G , Furosemide.
3. Those with long biologic half life(>12 hrs). Ex- Diazepam, Phenytoin.
4. For those which require large doses(>1 gm) Ex- Sulfonamides.
5. Extensive binding of drugs to plasma proteins will have long elimination half life and such
drugs generally do not require to be formulated to SRDF.
6. Those with cumulative action and undesirable side effects. Ex- Phenobarbital
7. Those with low therapeutic indices. ex- Digitoxin.
8. Those requiring precise dosage titration for every individual. Ex- Warfarin, Digitoxin.
9. In general a very highly soluble drug or a highly insoluble drug are undesirable for
formulation into SRDF product.
References
Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (Chapter 9:
Solid Oral Modified-Release Dosage Forms and Drug Delivery Systems)

Aulton's Pharmaceutics-The Design and Manufacture of Medicines by Michael

E. Aulton, Kevin M.G. Taylor (Chapter 31: Modified-release oral drug delivery)

Remington Education: Pharmaceutics by Shelley Chambers Fox (Chapter 13:

Oral delivery of modified release solid dosage forms)